The overall objective of this proposal is an increased understanding of respiratory sensitivity to environmental tobacco smoke (ETS). These proposed studies represent the logical outgrowth of our preliminary studies which showed that: 1) In a survey of healthy nonsmokers, a history of rhinitis symptoms after exposure to environmental tobacco smoke was reported by 40% of subjects. 2) Controlled challenge with sidestream tobacco smoke (STS) in an environmental chamber results in increased rhinitis symptoms and an increase in posterior nasal resistance in historically ETS sensitive subjects as compared to historically ETS-nonsensitive objects. 3) ETS sensitive subjects are more likely to be atopic by skin prick tests. 4) There is no increase in nasal lavage histamine following STS exposure; this suggests that mast cell activation is not the basis for ETS sensitivity. Studies in this proposal are aimed at testing the hypothesis that ETS sensitivity in humans represents a neurally mediated increased inflammatory response to the vapor phase component of STS. Other investigators have shown that a response to cigarette smoke in animals is mediated by C-fiber afferent neuron stimulation by the vapor phase component of smoke. We will first characterize the symptomatic, physiologic and inflammatory response to STS over a dose range found in indoor environments. Next, we will determine whether ETS-sensitive subjects are hyper-responsive to the organic vapor component of STS. We will explore the mechanism of ETS sensitivity by attempting to block the response to STS pharmacologically. We will then explore lower respiratory sensitivity to ETS, by determining whether STS causes decrements in lung function or increased reactivity under conditions of moderate exercise in ETS sensitive subjects. Finally, we will investigate the interaction between allergic illness and ETS. We will test the hypothesis that antigen challenge will increase the responsiveness to subsequent STS exposure. This latter hypothesis is based on clinical, anecdotal evidence and on animal causes prolonged depolarization of neurons. It is our opinion that an increased understanding of sensitivity to environmental tobacco smoke will result in a better understanding of non-allergic rhinitis and aid in the development of rational control and therapeutic measures for this prevalent condition.